Microneedle arrays formed from polymer films

ABSTRACT

An active agent can be administered transdermally to a patient by using a transdermal patch that has microneedles that are compositionally homogenous with a base layer. The transdermal patch can contain an active agent that can be delivered to a skin surface of a subject when the patch is applied.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Pat. Application Serial No.13/758,872, filed on Feb. 4, 2013, which is a divisional of U.S. Pat.Application Serial No. 12/187,268, filed on Aug. 6, 2008, now U.S. Pat.No. 8,366,677, which claims the benefit of U.S. Provisional ApplicationSerial Nos. 60/963,725, filed Aug. 6, 2007, and 60/994,568, filed Sep.19, 2007, the entirety of each of which is incorporated herein byreference.

BACKGROUND

This invention relates generally to the field of devices for thetransport of therapeutic or biological molecules into and across skintissue barriers, such as for drug delivery.

Drugs are commonly administered today through either the oral,parenteral, or transdermal routes of administration. One great challengeto transdermal administration is poor permeation of the active agentthrough the skin. The rate of diffusion depends in part on the size andhydrophilicity of the drug molecules and the concentration gradientacross the stratum corneum. Few drugs have the necessary physiochemicalproperties to be effectively delivered through the skin by passivediffusion, iontophoresis, electroporation, ultrasound, chemicalpermeation enhancers, and heat (so-called active systems) have been usedin an attempt to improve the rate of delivery. Furthermore, thecombination of the active agent, permeation enhancers, and certaincarriers have been used in order to try and achieve specific deliveryprofiles over a desired duration.

SUMMARY

Accordingly, the present invention provides for transdermal deliverydevices as well as methods for their manufacture and use. In oneembodiment, a transdermal delivery device is provided. The transdermaldelivery device includes a polymer layer which has microneedlesprojecting from one of its surfaces. The microneedles arecompositionally homogenous with the polymer base layer.

In another embodiment, a method for administering an active agenttransdermally is provided. First a transdermal delivery device isprovided. The transdermal device includes a polymer base layer havingmicroneedles projecting from one of its surfaces. The microneedles arecompositionally homogenous with the base polymer layer. An active agentis also included in the transdermal delivery device. The transdermaldelivery device is applied to a skin surface of a subject in order todeliver the active agent to the subject.

In yet another embodiment, a method of manufacturing a transdermal drugdelivery device having a microneedle array is provided. The methodinvolves providing a substrate and then applying a polymer solution tothe substrate to form a base layer. An exposed surface of the base layeris then disposed with a textured surface or template having elevatedpoints protruding therefrom such that the elevated points contact theexposed surface of the base layer. Exemplary textured surfaces includebut are not limited to arrays of metal pins or points as commonly usedin electronics or as on the surface of an ordinary rasp file. Thetextured surface is then distanced from the exposed surface of the baselayer such that the elevated points draw out tube-like projections fromthe exposed surface of the base layer. The base layer and the tube-likeprojections can be dried to form microneedle arrays. In some cases, themicroneedles can be hollow. In other embodiments, the microneedles maybe solid. The microneedle arrays can then be cut to form the transdermaldrug delivery device.

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1A-1C show a microneedle array device showing relative scale. FIG.1A illustrates a microneedle array shown is supported by a glasssubstrate, with a penny to show scale. Highly regular arrays of hollow,dissolvable microneedles are formed from a polymer solution film. Thearray shown has 248 microneedles in an 8 by 31 array, showing 2 or fewerdefective needles. FIG. 1B shows a close-up of the microneedles of anarray clearly showing internal channels in each needle. Solid needlesare also possible, by varying fabrication conditions. Bubbles in thebase film are similar to those believed to cause the hollows during theneedle forming process. The needle tips may be beveled at any angle bytrimming. FIG. 1C shows a needle loaded with fluorescein and under UVillumination. Microneedle array delivery devices may be formed withhollow needles suitable for loading with a variety of materials(“cargo”).

FIG. 2 shows a schematic of a microneedle array preparation. Needles areprepared from a polymer (e.g. polyvinyl alcohol (PVA)) film by “drawingout,” leaving a hollow tube. The ends are clipped to give desired shapeof needle end (and length). The resulting hollow tubes are “charged”with an active ingredient, such as nucleic acids (e.g. plasmid orsiRNA). The cured (hardened) microneedle array is inserted into theskin. In the aqueous environment of the epidermis, the needles softenand deform, and the inserted portion will separate (leaving the“charged” tips in the epidermis) as the backing material is removedafter an initial application period. As the PVA solution dissolves, thecargo is slowly released into the target epidermis.

FIGS. 3A and 3B show cross-sections of excised human skin showingpenetration by needles loaded with gentian violet. FIG. 3A shows amicroneedle delivery device loaded with gentian violet solution as avisual reporter (“cargo”) and was applied to fresh human skin explant(resulting from an abdominoplasty procedure) and then immediately placedinto tissue freezing medium (OCT) and cooled to -28° C. The sample wassectioned at an angle nearly parallel to the needle array geometry,allowing observation of multiple needles. The delivery device backingmaterial is visible as a layer between the OCT and the skin sample. Theleft needle is itself cross-sectioned, showing the gentian violetsolution loaded into the needle shaft. The middle needle appears topenetrate both the stratum corneum and the epidermis, with the needletip in full contact with the dermis. A third needle (on the right) isvisible but is out of the focal plane. FIG. 3B shows the gentian violetdelivered to human epidermis and dermis using the microneedles. TheGentian violet was detected using a fluorescent microscope under redfluorescence filters (excitation 546 nm; emission 580 nm). The skinsection was stained with DAPI to allow nuclei visualization.

FIGS. 4A-4C show in vivo imaging of individual microneedle penetrationsites and visualization in skin sections. FIG. 4A shows localizedfluorescence observed using the Xenogen IVIS 200 system to view the leftmouse footpad of a mouse to which had been applied a microneedle arrayloaded with siGLO Red (a fluorescently-tagged siRNA mimic, 0.05 µg perneedle). FIG. 4B shows fluorescence microscopy of mouse footpadlongitudinal skin sections. FIG. 4C shows fluorescence microscopy ofmouse footpad cross sections of needles loaded with siGLO Reddemonstrating delivery to the epidermis. All sections were stained withDAPI to visualize nuclei (bar = 10 µm).

FIGS. 5A-5F show several fluorescence microscopy images of mouse footpadskin sections demonstrating siGLO Red (fluorescently-labeled siRNAmimic) delivery to the epidermis (or dermis) following administrationusing a loaded microneedle array. FIGS. 5A and 5B show that lateraldiffusion dominates the transport of material outward from the deliverysite (~90 min timepoint), with comparatively little red fluorescencevisible in the dermis (bar = 20 µm). FIGS. 5C and 5D show that diffusionwas occasionally detected in both the dermis and epidermis (bar = 10µm). FIGS. 5E and 5F where taken 30 min after application and show thatlonger needles are able to deliver to the dermis. All sections werestained with DAPI to visualize nuclei (bar = 50 µm).

FIGS. 6A and 6B show expression of fLuc reporter gene in mouse ear andmouse footpad administered by a microneedle array transdermal deliverydevice. FIG. 6A shows an ear on the right that was “injected” with aneedle array loaded with ~50 µL fLuc expression plasmid (10 mg/mL inPBS) per needle. The ear on the left was “injected” with the STMNAdelivery device loaded with PBS only. Needles were inserted into the earfor 20 min. After 24 h, luciferase expression was determined followingIP luciferin injection by whole animal imaging using the Xenogen IVIS200in vivo system. FIG. 6B shows footpad delivery. Reproducibility ofmicroneedle array-mediated delivery of fLuc reporter plasmid wasassessed by treating multiple mice. Left footpads were treated withmicroneedle arrays (12 needles) loaded with luciferase expressionplasmid. Luciferase expression is observed in the left footpadsfollowing IP administration of luciferin, while right footpads, whichreceived microneedles loaded with PBS vehicle alone, do not.

DETAILED DESCRIPTION

Before particular embodiments of the present invention are disclosed anddescribed, it is to be understood that this invention is not limited tothe particular process and materials disclosed herein as such may varyto some degree. It is also to be understood that the terminology usedherein is used for the purpose of describing particular embodiments onlyand is not intended to be limiting.

In describing and claiming the present invention, the followingterminology will be used.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a microneedle” includes reference to one or more microneedles, andreference to “the polymer” includes reference to one or more polymers.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint.

The term “subject” refers to a mammal that may benefit from theadministration using a transdermal device or method of this invention.Examples of subjects include humans, and other animals such as horses,pigs, cattle, dogs, cats, rabbits, and aquatic mammals.

As used herein, the term “active agent” or “drug” are usedinterchangeably and refer to a pharmacologically active substance orcomposition.

The term “transdermal” refers to the route of administration thatfacilitates transfer of a drug into and/or through a skin surfacewherein a transdermal composition is administered to the skin surface.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result.

As used herein, sequences, compounds, formulations, delivery mechanisms,or other items may be presented in a common list for convenience.

However, these lists should be construed as though each member of thelist is individually identified as a separate and unique member. Thus,no individual member of such list should be construed as a de factoequivalent of any other member of the same list solely based on theirpresentation in a common group without indications to the contrary.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 0.5 to 10 g” should beinterpreted to include not only the explicitly recited values of about0.5 g to about 10.0 g, but also include individual values and sub-rangeswithin the indicated range. Thus, included in this numerical range areindividual values such as 2, 5, and 7, and sub-ranges such as from 2 to8, 4 to 6, etc. This same principle applies to ranges reciting only onenumerical value. Furthermore, such an interpretation should applyregardless of the breadth of the range or the characteristics beingdescribed.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention belongs. Although any methods, devicesand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, representativemethods, devices, and materials are described below.

As discussed above, the present invention provides transdermal deliverydevices as well as associated methods of manufacture and use. In oneembodiment, a transdermal delivery device is provided. The transdermaldelivery device includes a polymer layer which has microneedlesprojecting from one of its surfaces. The microneedles arecompositionally homogenous with the polymer base layer.

The polymer which forms the polymeric layer and the microneedles can beselected from a variety of polymers known in the transdermal drugdelivery arts. In one embodiment, the polymer can be bio-absorbable orbiodegradable. Non-limiting examples include polyvinyl alcohol (PVA),polyacrylates, polymers of ethylene-vinyl acetates, and other acylsubstituted cellulose acetates, polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, polyethylene oxide, chlorosulphonatepolyolefins, poly(vinyl imidazole), poly(valeric acid), poly butyricacid, poly lactides, polyglycolides, polyanhydrides, polyorthoesters,polysaccharides, gelatin, and the like, mixtures, and copolymersthereof. In one embodiment, the polymer can be an adhesive polymer. In apreferred embodiment, the polymer is polyvinyl alcohol.

Depending on the type of polymer selected, the concentration of thepolymer used can be varied in order to obtain the desired microneedleforming properties. In one embodiment, the concentration of thepolymeric solution which is used to form the polymeric base layer andthe microneedles can have a polymer concentration of from 1 wt% to 50wt%. In a one embodiment, the polymer can be polyvinyl alcohol and theconcentration in the polymeric solution can be 20 wt%.

The microneedles of the microneedle arrays are made from the samematerial as the polymer base thereby making them compositionallyhomogenous with the polymer base. The microneedles can be oriented at anangle to the polymer base or they can be configured to be perpendicularto the polymer base. It is preferable that the microneedles are orientedperpendicularly to the polymer base in order to facilitate insertion ofthe needles into skin surface by pressure normal to the surface. It isalso possible to produce and provide a microneedle array which hasmicroneedles with different angular configurations or different needlelengths. In one embodiment, the microneedles can have a length of fromabout 10 µm to about 10000 µm. In another embodiment, the microneedlescan have a length of from about 50 µm to about 1000 µm. In anotherembodiment, the microneedles can have a length of from about 75 µm toabout 500 µm.

Depending on the active agent or drug being delivered as well as thedesired length of time of delivery, and the polymer used to form themicroneedles, the microneedles can be configured to soften or dissolvesuch that they detach and are left in embedded in the skin. When themicroneedles are configured to be left in a subject even after removalof the polymer base layer, the polymer can be a biodegradable orbio-absorbable polymer. Microneedles which are detached and leftembedded in the skin can provide sustained or extended release of theactive agent being delivered by the needles. In one embodiment, formedneedles can be further loaded by momentarily contacting the needle tipsto a second polymer solution, which may contain an active agent. Whenthe needles are withdrawn, a residue of the second polymer solutionremains on the tips, or within the tip of the hollow portion of theneedles. If this second polymer solution possesses lowerwater-solubility characteristics that differ from the primary polymercomposing the needles, the tip represents a payload that is depositedwhen the microneedle detaches in the skin, in a manner similar to aharpoon tip. The lower solubility of the payload tip may provide anextended release characteristic if an active agent is incorporated intothe tip polymer.

The microneedles can be manufactured to be hollow or solid. When themicroneedles are hollow, an active agent or active agent composition canbe loaded into the hollow portion of the microneedle which can then bedelivered by the needle to a subject. The term “hollow” refers to aregion in the interior of the microneedle having a diameter which issufficient in size to allow the passage of liquid or solid materialsinto or through the microneedle. The hollow portions of the needle can,but are not required to, extend throughout all or a portion of theneedle. In one embodiment, the hollow region can have an opening at thetip of the microneedle. When the microneedles are solid, an active agentor active agent composition can be loaded onto the exterior surface ofthe microneedle. Hollow needles can be potentially loaded with largerquantities of active agent payload than is possible for solid needles ofthe same dimension.

The microneedle arrays contained in the transdermal devices of thepresent invention can be configured to deliver a wide variety of activeagents including active agents intended for topical, local, and/orsystemic delivery. Generally, any drug or active agent which can beeffectively delivered transdermally can be delivered using themicroneedle arrays of the present invention. In one embodiment, theactive agent can be nucleic acid material, including but not limited tosingle or double stranded DNA/RNA, plasmids, or the like.

The active agents can be loaded or incorporated into the microneedlearrays in a number of ways. In one embodiment, the active agent can beloaded into the hollow region of the needle. Loading into the hollowregions can be done through capillary action, a pressurized reservoir,or any other means which can be used without damaging the microneedlearray. One method of loading the hollow needles can be to bring theneedle tips into momentary contact with a solution of an active agent ina volatile material such as water or ethanol. When the tips touch thesurface of an appropriate liquid, the liquid can wet into the tips bycapillary action, and an aliquot is introduced into only the needle tip,which is believed will produce the most efficient use of the activeagent, avoiding waste of material in the non-penetrating portion of thearray.

The active agent can also be incorporated into the microneedle throughincorporation into the polymer solution from which the microneedle andthe polymer base layer are formed. When the active agent is incorporatedinto the microneedle in this manner the active agent is alsoincorporated into the polymer base layer. When the active agent isincorporated directly into the polymer of the microneedle, themicroneedles deliver the drug in a similar manner as the matrix layer intraditional transdermal matrix patches. However, the microneedles mayprovide the additional benefit of providing local disruption of skinbarrier structures, facilitating the entry of drugs which might notnormally penetrate skin in a transdermal matrix patch delivery system.

In another embodiment, the active agent(s) can be incorporated into themicroneedle by first loading an active agent solution onto theprotrusions of the textured surface or template used to draw out theneedles from the base layer. In this case, the active agent(s) aretypically observed to be localized in the needle structure, with littleor no migration into the base layer. A variety of other methods ofloading the needles may be apparent to one of ordinary skill in the artto which this invention belongs, and these methods may include contactwith solutions, or vapor or powder forms of active agent compositions.Choice of methods by which needles are loaded may be dictated by theparticular active agents and details of the desired application for thatparticular microneedle array product.

The microneedle arrays can be incorporated into a variety of transdermaldelivery devices such as transdermal patches. In one aspect of theinvention, the polymer base layer of the microneedle array can beattached to a backing layer to form a transdermal patch. In anotheraspect, the polymer base layer can be associated with or attached to anactive agent reservoir from which active agent can be delivered throughthe microneedles to a subject. The reservoir layer can be a liquidreservoir or a hydrogel reservoir or any other reservoir type known inthe arts so long as the reservoir can adequately deliver the activeagent to the microneedles. Other material may also be incorporated intothe transdermal delivery devices of the present invention such aspermeation enhancers, controlled-release membranes, humectants,emollients, and the like.

The microneedle arrays can be used as or incorporated into transdermaldelivery devices to administer active agents transdermally. Themicroneedle arrays of the transdermal delivery devices can be applied toa skin surface of a subject in order to deliver the active agent to thesubject. The administration can be for a sustained or an extended periodof time. Sustained delivery of the active agent can be accomplished byusing microneedle arrays in which the microneedles can be detached andremain in the skin of the subject even after removal of the rest of thetransdermal delivery device, including the polymer base layer.Microneedles left in the skin of a subject act as active agentreservoirs and can delivery active agent even after the transdermaldelivery device is removed.

The microneedle arrays used in the transdermal delivery devices of thepresent invention can be made in any manner known in the art so long asthey comply with the other requirements set forth above. One method ofmanufacturing or forming the microneedle arrays is provided herein. Themethod involves providing a substrate and then applying a polymersolution to the substrate to form a base layer. An exposed surface ofthe base layer is then disposed with a textured surface having elevatedpoints protruding there from such that the elevated points contact theexposed surface of the base layer. The textured surface is thendistanced from the exposed surface of the base layer such that theelevated points draw out hollow tube-like projections from the exposedsurface of the base layer. The textured surface can be made of anymaterial known in the field and can be configured in any manner whichallows it to contact the base layer and draw out the microneedleprotrusions as described herein. Once drawn out, the microneedleprotrusions can be sharpened or otherwise shaped using any method knownin the art.

The base layer and the hollow tube-like projections can be dried to formmicroneedle arrays. The microneedle arrays can then be cut to form thetransdermal drug delivery device. Methods for cutting or forming thetransdermal drug delivery device are well known in the art, includingbut not limited to die cutting or other physical shearing, thermalmelting, thermal degradation, laser ablation, chemical degradation,dissolution, freeze fracture, sonication of the template, or any otherphysical or chemical known in the art. It is important to note that themanufacture of the needles can be done in single batch or continuousbatch methods. When a continuous manufacturing method is used, anymechanized means known in the art can be used. For example, the surfaceused to draw out the microneedle protrusions could be a roller havingnumerous rows of protrusions which are configured to contact and drawout the microneedles from the base layer. Other mechanized and automatedmanufacturing techniques and technologies used in the manufacturing artscan be retrofitted and used in the production of the microneedles of thepresent invention.

The substrates used in the manufacture of the microneedle arrays can beany solid or porous material onto which a polymer solution can beapplied. Non-limiting examples of substrate layers include glass,backing layer materials including woven and non-woven material, etc.

As discussed above, a variety of polymers and polymer solutionconcentrations can be used in order to form the microneedles of thepresent invention. The polymer solution can be applied to the substratein order to form a polymer base layer. The polymer base layer generallyhas a thickness from about 0.5 mm to about 5 mm. In one embodiment, thepolymer base layer can have a thickness of from 0.5 mm to about 2 mm. Inon embodiment, the polymer base layer has a thickness of about 1 mm.

The textured surface which contacts the exposed surface of the polymerbase layer has raised regions or points which contact the polymer baselayer. The raised regions can be regularly spaced on the texturedsurface in order to form regularly spaced microneedles. The number ofraised regions on the textured surface and correspondingly the number ofmicroneedles formed can be a factor of the active agent or drug beingdelivered as well as the amount or dosage of the active agent. Such adetermination could be made by one of ordinary skill in the art. FIG. 1shows an array of microneedles formed using the method described hereinfrom a 30 wt% polyvinyl alcohol solution.

The length of the microneedles formed is a function of the distance thatthe textured surface is distanced or drawn away from the polymer baselayer. As discussed above, the microneedles can have a length of fromabout 10 µm to about 10000 µm. FIG. 2 shows a schematic of the drawingprocess which can be used to form the microneedle arrays. After themicroneedles are drawn or formed, the polymer base layer and themicroneedles of the array can be dried by baking, blowing, other dryingmeans, or combinations thereof. In one embodiment, drying of themicroneedles and the polymer base layer can occur during the distancingstep in which the microneedles are formed. It is noted that when loadingof the microneedles occurs after the initial drying it can be desirableto perform an additional drying or baking step subsequent to the loadingof the needles with an active agent composition. Baking the needles atabout 80° C. for about 1 hour increases their rigidity, formingmicroneedles sufficiently rigid to penetrate through the stratum corneumand into deeper skin layers (FIG. 3 ). Use of increased air flow rates,or reduced pressure as in a vacuum oven may decrease the temperature andcuring time required.

While not wishing to be bound by any particular theory, generally, theincreased needle rigidity required for skin penetration is understood tobe a function of solvent evaporation rather than a chemicaltransformation, and any process by which solvent may be removed isunderstood to accelerate needle hardening. Further, it is believed thatthe shape and structure of the needles is highly dependent on thedynamics of the drying process. The length of the needles is directlydependent upon the distance to which the template is retracted from thesurface of the polymer film base layer from which the needles arepulled. However, the rate at which the template is retracted and rate atwhich the film dries act together to determine the morphology of theneedles formed. If the template is withdrawn too quickly relative to thedrying rate, the strand of polymer solution connecting each templateprotrusion may be stretched beyond its capacity to flow and deform, andthe strand may fail, prematurely separating the template protrusion fromthe film. If the drying rate is too fast relative to the rate ofretraction, the entire film surface may dry to form an elastic filmrather than an inelastically deformable or flowable gel. If the filmdries sufficiently to behave as an elastic solid before the templateprotrusion is completely withdrawn, the film may tear or separate fromthe substrate, producing an unacceptably deformed or non-uniform needlearray. However, between these two extremes, lies a range of acceptabledrying rates relative to any particular rate of retraction of thetemplate protrusions from the base polymer solution film. In oneembodiment the template can be retracted from the base at a rate of 0.1mm/s to 100 mm/s with a heated airflow drying the of 0.1 m/s to 10 m/sat a temperature of 0° C. to 100° C. In another embodiment, the templatecan be retracted from the base at a rate of 1 mm to 50 mm/s with aheated airflow drying the of 0.5 m/s to 7 m/s at a temperature of 20° C.to 70° C. In yet another embodiment, the template can be retracted fromthe base at a rate of 2 mm/s to 15 mm/s with a heated airflow drying theof 0.75 m/s to 5 m/s at a temperature of 25° C. to 50° C.

When the drying rate of the polymer film is well matched to the rate oftemplate retraction in the present invention, the base polymer filmremains fluid and inelastically deformable, while the strands formedbetween the template protrusions and the base film dry more quickly thanthe base layer, and rapidly become inelastic, which permits longerfiber-like needle structures to be drawn out of the still wet film. Ineffect, the drier elastic portion of the strand plays the role of thetemplate projections relative to the wetter inelastically deformablebase layer. Without being limited by any particular theory, it isbelieved that the strands dry more quickly than the base layer primarilydue to a large ratio of drying surface area versus internal volume, ascompared to the base layer which has a lower drying surface area versusits internal volume. Additionally, air flow patterns further away fromthe film surface may very likely contribute to this effect, particularlyif drying is promoted by flowing air over the needles as they areformed.

Any method may be used to promote or control the drying process,including methods that use air flow, heat or cooling, pressurization orvacuum, humidity, or any other method familiar to those skilled in theart of polymer processing. Further, to the extent that the polymersolution rheology or elasticity may be influenced by factors other thansimple drying, such as temperature, chemistry, photochemical effects,sonic or vibrational energy, or other methods known to those skilled inthe art of polymer processing, these methods may also reasonably beapplied to accomplish the same effects in the needle drawing process.

As the needles are drawn out from the base polymer layer as describedabove, it is understood that as the surface of the base film dries toform an elastic layer, this layer becomes more and more pulled onto thestrands being drawn from the film. If the air flow is such that thesurface of the base layer dries to relative inelasticity in the last oneor two millimeters of the template withdrawal, it is deformed moresubstantially in these last millimeters of withdrawal, to form a widerbase. Surprisingly, it is observed that the formation of this wider baseis accompanied by the formation of a hollow space within the needle.Without being limited by any particular theory, it is believed that thetension produced by the withdrawal of the protrusions from the filmduring its transition to elastic behavior creates a region of lowerpressure between the drying surface and the wetter solution beneath thefilm surface, and that this lower pressure induces evaporation of someof the water of the solution to form a pocket rich in water vapor.Independent of the actual cause or contents of the void area, a hollowneedle is the result.

Another aspect of the incorporation of the drying surface into theneedle base is that if an active agent is distributed only upon thesurface of the polymer solution layer. For example, by applying a smallquantity of a solution of the active agent within a more volatilematerial such as ethanol, it is observed that a disproportionatequantity of the active agent is incorporated into the base of theneedles. This is readily observed by use of a colored active agent suchas fluorescein.

EXAMPLES Example 1 - Production of Microneedle Array

Microneedle arrays were prepared according to the following steps:

1) A 0.3 gram aliquot of approximately 30% polyvinyl alcohol [PVA](Spectrum Chemicals, Gardena, CA) solution in water was spread in auniform thin layer to cover approximately the entire surface of astandard glass microscope slide (roughly 25 by 75 mm).

2) A common rasp-type file was placed with the working surface facing upon the laboratory bench, and the slide was lowered PVA-side down, sothat the PVA layer was brought into contact with the file workingsurface. The slide was then gently pressed down so as to wet the tips ofthe file points with the PVA solution.

3) A common hair dryer set to low was used to direct a stream ofapproximately 60° C. air flowing at approximately 4 m/s over the fileand slide thus assembled from a distance of about 1 foot, blowinghorizontally along the laboratory bench surface, with the intent to dryand heat the needles as they were formed.

4) Immediately after directing the warm air stream over the work piece,the slide was carefully removed from the file by lifting it straight upfrom the file surface to a height of approximately 15 mm above the filepoints. The file was held in place, so that it was not pulled up byadhesion to the slide. From each file point, a hollow tube was drawn upfrom the film surface, the hollow being formed from a bubble at theneedle base, apparently created or enhanced by the pulling action.

5) The slide was kept positioned exactly over the file to avoid flexionor distortion of the newly formed needle structures, and the warm airstream was continued for about 10 minutes to dry the needles and the PVAfilm from which they had been formed.

6) The air stream was stopped, and the needles were cut off of the filesurface by running a standard single-edged razor blade parallel to thefile surface, just above the file rasp tips. The needles were smoothlyand easily sliced just above their point of contact with the file rasptips. The rasp tips were spaced such that a regular array of needles wasformed in the film in 8 columns of 31 rows each, forming 248 needles, ofwhich 2 were either bent or deformed such that they appeared not usefulas needles, and the remaining 246 needles appeared capable.

7) The PVA film was removed from the glass substrate by sliding astandard single-edged razor blade between the edge of the film and theglass, which permitted a smooth separation, something between peelingand slicing the film away from the glass.

8) The needles were trimmed to a height of about 3 mm using a pair oftypical cuticle-type scissors purchased from the local Longs Drugstore.Trimming was performed under an inspection microscope to facilitatevisualization of the small structures, and the needle tips were cut atapproximately 45 degrees to normal, to form a sharp, beveled tip.

9) Needles were loaded with pcDNA3.1 fLuc expression plasmid (10 mg/ml)at approximately 200 ng/needle in phosphate buffer solution (PBS) andthen baked at 90° C. in a typical consumer toaster oven with the dooropen for about 60 minutes, then cooled for 10 minutes. This baking stepwas performed to dry and harden the needles to sufficient rigidity forskin penetration. A similar control needle array was prepared using thecarrier (PBS) alone.

10) The needle arrays (fLuc expression plasmid or PBS control) werepressed into the ears of an anesthetized (isoflurane) mouse using fingerpressure for approximately 20 minutes at which time the needle arrayswere removed. The mice were allowed to sleep for an additional 25minutes.

11) After 24 hours, the mouse was administered 100 µl of 30 mg/mlluciferin by intraperitaneal injection. Following a 10 minute incubationto allow biodistribution of the luciferin, the mice were anesthetizedwith isoflurane and imaged for 5 minutes (light emission captured) usinga Xenogen IVIS200 imaging system, which showed unambiguous signallocalized at the site of microneedle administration, demonstratingexpression of the injected plasmid.

Example 2 - Manufacture of a Loaded Microneedle Array

Microneedle arrays of the present invention were prepared as set forthbelow:

1) A solution of polyvinyl alcohol (PVA) (Spectrum Chemical, Gardena,CA) is prepared by dissolving 19 grams of dry PVA in 81 grams ofdistilled water (DI) at 80C for 24 hours, stirring the thick solutionmanually every 3 hours after the first 12 hours. The solution istransferred hot to suitable containers for subsequent dispensing (suchas two 50 mL plastic syringes) and cooled to room temperature prior touse.

2) A solution of Carboxymethylcellulose Sodium solution (CMC) (SpectrumChemical, Gardena, CA) is prepared by dissolving 2 grams CMC in 98 gramsof DI at 80C for 24 hours, stirring continuously on a hotplate/magneticstirrer. The solution is transferred to a glass jar with a screw cap andcooled to room temperature before use.

3) An ordinary microscope slide measuring 25 by 75 mm by 1 mm thick iscoated with roughly 0.5 grams of the 2% CMC solution described above bythe following method. The microscope slide held by forceps at one short(25 mm) edge, and dipped into the CMC solution until roughly 55 mm arebelow the surface, with 20 mm remaining unwetted by the CMC. The slideis withdrawn from the CMC solution and one side is scraped off using aspatula or other straight edge. The scraped side is then wiped against alaboratory wipe or other absorbent material to dry and remove themajority of CMC solution, leaving a roughly cleaned bottom face, with atop face coated in the CMC solution. The slide is placed on a levelsurface in an air stream of 3 m/s at 50° C. until visibly dry, roughly15 minutes. The CMC solution is sufficiently fluid to flow across thesurface, producing a roughly uniform coating on the slide. The driedlayer produced by this method serves as a release layer for thesubsequent PVA coating to be applied for needle formation. The finaldried weight of the CMC film is approximately 0.01 g, and the filmthickness is apparently thinner than 0.1 mm as gauged by eye.

4) A microscope slide that has been pre-treated with CMC as describedabove is coated with PVA preparatory to forming needles by the followingprocedure. A roughly 0.75 gram aliquot of an 19% PVA solution isdeposited on one end of a CMC pre-treated microscope slide, and spreadto a thickness of 0.5 mm using a spatula or similar straight edge. Asufficiently uniform 0.5 mm layer thickness is produced by the use oftwo 1.5 mm rails on either side of the slide. The underlying dry CMClayer thickness is apparently negligible compared to the thickness ofthe subsequent PVA layer, and is not considered in the applicationthickness of the PVA layer. The layer produced is roughly 40 by 25 mmwide, and 0.5 mm thick.

5) The microscope slide coated with PVA solution described above ismounted in a chuck or clamped to prevent it from moving. By means of amotion control device such as a pneumatic actuator, a template of rigidpins is brought into contact with the PVA solution to a depth of atleast 0.2 mm. Heated air is flowed across the substrate and pins atapproximately 35° C. and 1.0 m/s and the pins are permitted to remain inthe drying film for about 5 seconds and then retracted 1 cm at a rate ofabout 5 mm/s. About halfway through the retraction, after 10 seconds, anadditional airflow is introduced at 50° C. and 2.0 m/s. The initialeffect of retracting the pins is to produce stringlike fibers from thePVA solution. As the PVA solution is pulled from the base layer by thepins, the airflow dries the thin fibers much more rapidly than the baselayer. However, when the airflow is increased halfway through, thefibers dry much more rapidly, and the drying region is understood to bemuch closer to the base layer, and a thicker fiber results.Surprisingly, under the conditions described above, this thicker fiberdevelops a void, likely due to heated water vapor, and subsequentretraction of the pins results in formation of a hollow tube rather thana sealed fiber. If the stronger heated airflow is initiated too early,the base film dries too quickly and sheets of PVA film are pulled awayrather than discrete fibers, even to the point of separating from theglass slide. If the stronger heated airflow is not initiated, hollowfiber formation does not occur reliably, and the solid form is thetypical outcome. The form of the needles is strongly influenced by theuniformity, temperature, and rate of air flow, and these must beoptimized to produce reproducible desired results. The values providedhere are exemplar, and any particular apparatus may require slightadjustments to these parameters.

6) The stronger heated airflow is maintained for approximately 15minutes until the base PVA layer has dried to a thickness ofapproximately 0.1 mm, and is an elastic solid rather than a liquid. Thearray is preferably further dried at 25° C. for 24 hours atapproximately 30-50% humidity, and then separated from the glasssubstrate by use of a razor blade or similar sharp implement. The CMClayer permits easy removal by this method, and prevents the PVA frombonding more permanently to the glass.

7) The array of needles prepared as described above is separated fromthe template pin array by slicing the needles with a razor blade. It isconvenient to slice the needles close to the template pins to leaveminimal PVA residue on the pin array, which may be rapidly cleaned byimmersion in water at 80° C. The needles are then manually trimmed withminiature shear-type scissors, such as manicure scissors, to produceneedles of a desired length and tip-bevel. After an initial 24 hour 25°C. drying time, needles and backing material are easily cut, and veryflexible, although resilient. It is easier to cut the needles beforefurther drying, but not required.

Steps 8-10 may be included in the original manufacture or can beperformed at a later time.

8) Needles may be loaded by bringing the needle tips into contact with asolution of the desired payload, or any liquid form of the payload.Lower viscosity (such as ethanolic) 1-100 cSt solutions are most easilyloaded, but higher viscosity up to around 1000 cSt aqueous solutions ofmacromolecules may also be loaded by this method. A preferred method ofloading individual needles is to use a plastic dispensing pipette tip orsimilar, which permits entry of the needle into the tip, but inhibitsthe tendency of solution surface tension to wet across the PVA baselayer, and impedes evaporation of the payload solution from thedispenser. Multiple needles can be loaded simultaneously by use ofmultiple tips spaced at intervals aligned with needle spacing.

9) After loading, the PVA matrix forming the needle structuresfrequently becomes hydrated and softens. In order to prepare the needlesfor use in injecting the payload material, further drying is required.This drying may be accomplished by simple heating in an airflow, but toprevent degradation of sensitive biological molecules it is useful touse a vacuum oven. Typically 12 hours drying at -20 lbs vacuum and 50°C. produces highly rigid needles that are useful for injection.

10) If the payload in the needles was introduced in aqueous solution,the sharp tips of the cut needles may be solubilized in the loadingprocess, and the final dried form may show rounding of the initiallysharp tip. In such case, it is useful to re-trim the needle tips toproduce a freshly cut sharp edge following the final drying step.

Example 3 - Loading Hollow Microneedles With an Active Agent

Hollow microneedles, such as those formed by the method of Examples 1 or2 can be loaded with an active agent. A method of loading such hollowneedles is to bring the needle tips into momentary contact with asolution of an active agent in a volatile material such as water orethanol. When the tips touch the surface of an appropriate liquid, theliquid can wet into the tips by capillary action, and an aliquot isintroduced into only the needle tip, which is believed will produce themost efficient use of the active agent, avoiding waste of material inthe non-penetrating portion of the array. After loading, the needles canbe baked at about 100° C. for about 1 hour to increase their rigidity,and they have been found to be sufficiently rigid to penetrate throughthe stratum corneum and into deeper skin layers.

When the needles are significantly hydrated, they frequently soften to aflexible, rubbery state, retaining their basic shape and orientation,but no longer sufficiently rigid to penetrate skin. Longer exposure tosolvent can potentially deform or dissolve the needles, but the shortexposure to the low volumes used for loading does not typically producethat result. If the needles are rubbery after loading, a seconddehydration process is required to produce sufficient rigidity andhardness for skin penetration. Generally this takes place through bakingat around 100° C. for 1 hour, but it is expected that desiccation by adrying agent, reduced pressure, or any other process would achieve asimilar effect.

Example 4 - Identification of Polymers for Use in Preparing Microneedles

Aqueous solution concentrations (10-50% weight/volume or maximumflowable at 25° C.) of various USP polymer materials acceptable forparenteral use for fiber-extrusion/draw characteristics using astandardized air flow of 5 cfm at 50° C. were prepared. Suitability forfiber draw can be determined by capability of the polymer solution toform a stable, reproducible nascent fiber structure of at least 1 cm(various polymers are expected to require different working speeds underarbitrary conditions, but a suitable candidate material should exhibitthis minimum capability). Polymers to be tested include, but not limitedto, the following: alginic acid, carboxymethylcellulose,hydroxypropylmethylcellulose, gelatin, guar gum, gum acacia, polyacrylicacid, polyvinyl alcohol, and polyvinylpyrrolidone, all available fromSpectrum Chemical (Gardena, CA).

Example 5 - Identification of Possible Solution Concentrations

The solutions of Example 3 were tested to determine which of thesolution has the best dry film qualities. Amounts of each of thesolutions can be formed on glass substrates to form films having 1 mmfilm thickness over a 25 mm by 75 mm area. The films are then dried bybaking at 90° C. for 1 hour and inspected for bubble formation, which isan indicator of the relative water permeability of the drying filmsurface. The films are then cooled, and the cooled films are thenqualitatively ranked regarding the following characteristics: difficultyof removal from glass substrate, ductility, brittleness and stiffness.Any materials that produce films that are insufficiently rigid to span a5 cm gap unsupported can be deemed unsuitable. The films are alsoqualitatively ranked by resistance to shear and slice cutting bystandard scissors and by razor blade, providing an indication of workingresistance and film toughness.

Example 6 - Testing of the Dissolution of the Films

Films identified in Example 4 are tested and quantitatively ranked withregard to their dissolution rate. Materials that produce films thatcompletely dissolve within 10 seconds are generally not as desirable.Time to non-rigidity and time to flowability are recorded as a possiblebasis for predicting needle solution dynamics expected after injection.

Example 7 - Testing Polymer Solutions for Needle Formation

Films of each solution are prepared as in Example 4, and templateprotrusions (8 columns by 31 rows of points) are contacted and withdrawnin a standard airflow of 50 cfm at 50° C., using a draw speedappropriate to each material as identified in Example 3. Resultingarrays will be evaluated with respect to needle dimensions andmorphology, with preference given to straight, tapered, hollow needleswith tip cross-sectional area being approximately 10% of the basecross-sectional area. Candidate material is selected, based on qualityof needle array, further qualified by dissolution and rigiditycharacteristics relative to other materials and by subjective evaluationof ease-of-workability.

Example 8 - Identification of Optimal Needle Formation Conditions

Test solutions of 20%, 30%, 40%, and 50% (or maximum flowable at 25° C.)concentration are prepared for use in needle drawing as in Example 6under several airflow conditions including 1) 50 cfm at 50° C., 2) 100cfm at 50°, and 3) 50 cfm at 80° C. The relative draw speed required foroptimal needle formation under each airflow condition, 5 replicates, isobserved and recorded. This data identifies a rough processconcentration, temperature, and airflow window. Conditions capable ofgood needle characteristics with maximum draw speed will be selected asoptimal.

Example 9 - Identification of Optimal Pre-Bake Drying Conditions

Needle arrays as prepared and tested in Example 7 are tested to identifyoptimal pre-bake drying times. After drawing, the arrays are dried inplace under airflow identical to the draw process for various times.Arrays are then be dried at 5, 10, 20, or 40 minutes under this airflowand separated from glass substrates. Optimal drying conditions will beidentified on the basis of best substrate removal characteristics.

Example 10 - Identification of Optimal Curing Conditions for LoadedMicroneedles

Microneedle arrays as described in Example 8 are manually trimmed to 3mm length, with 2 sets of the 8 columns each trimmed at nominal tipbevels of 0 (flat), 30, 45, and 60 degrees. Needles are then loaded with5 µL ethanolic solution of 2% Gentian Violet (Spectrum Chemicals) and 5%fluorescein (Spectrum Chemicals) (approximately 50 nL per needle).Groups of 5 arrays are pre-weighed, baked at temperature of either 60°C. or 80° C., for 30, 40, 50, 60, or 70 minutes and weighed then again.Needles are then qualitatively evaluated for rigidity for each set, withoptimal conditions identified as those producing maximum rigidity withthe shortest cure time. Any melting or discoloration of arrays willcause this bake condition to be rejected. Rigidity is expected tocorrelate with moisture loss, indirectly measured by change in mass. Anyneedle arrays observed to be insufficiently rigid are re-cured at thesame temperature in 10 minute increments until minimum required rigidityis attained. Curing temperature and duration are compared in thepresence or absence of a vacuum.

Example 11 - Testing of Needle Penetration and Active Agent Delivery

Needle array assemblies as described in Example 9 are applied to humanskin explants (resulting from abdominoplasties of de-identified patientswith informed consent) and left in the skin for 1-60 min. Explants (withor without the needle array) are then frozen in OCT and sectioned usinga Leica Jung Frigocut 2800E cryotome. Sections are then mounted onmicroscope slides using Histomount (Sigma) with DAPI stain forvisualization of nuclei. Sections are analyzed for needle penetrationand depostition of fluorescein and gentian violet by brightfield andfluorescence microscopy (Zeiss AXIO Observer A.1).

Example 12 - Delivery of Fluorescently-Labeled siRNA Using Microneedles

Microneedle arrays are loaded with 10 mg/mL siGLO Red siRNA (Dharmacon#D001830-02) or Cy3-labeled K6a siRNA in water as described forfluorescent dyes in Example 9. The loaded microneedle arrays are appliedto human skin and left in the skin for 1-60 min. Treated explants arefrozen in OCT and sectioned (7-10 micron) using a Leica Jung Frigocut2800E cryotome. Sections are mounted on microscope slides usingHistomount (Sigma) with DAPI stain for visualization of nuclei. Sectionsare analyzed for Cy3 expression using Zeiss Axio Observer.A1fluorescence microscope equipped with the DAPI and DsRed filters.

Example 13 - Penetration of Microneedles Into Human Skin

A microneedle array in the transdermal delivery device loaded withgentian violet solution was applied to fresh human skin explant(resulting from abdominoplasty procedure) and immediately placed intotissue freezing medium (OCT) and frozen to -28° C. The sample wassectioned at an angle nearly parallel to the needle array geometry, andmultiple needles were observed (FIG. 3 ). In FIG. 3 , the microneedlearray transdermal delivery device backing material is visible as a layerbetween the OCT and the skin sample. The left needle is itselfcross-sectioned, showing how the violet solution was drawn into theneedle shaft by capillary action. The needle at picture center of FIG. 3appears to penetrate both the stratum corneum and the epidermis, withthe needle tip in full contact with the dermis. A third needle isvisible at right (out of the cut plane) and is apparently penetrating toa similar depth.

Example 14 - Administration of fLuc to a Mouse Ear Using MicroneedleArrays

The ear on the right was “inj ected” with a microneedle arraytransdermal delivery device loaded with ~50 nL fLuc expression plasmid(10 mg/mL in PBS) per needle. The left ear was “injected” with amicroneedle array transdermal delivery device loaded with PBS only toact as a control. The microneedles were inserted into the ear for 20min. After 24 h, luciferase expression was determined following IPluciferin injection by whole animal imaging using the Xenogen IVIS200 invivo system. FIG. 4 shows the expression of fLuc reporter gene in themouse ear.

Example 15 - Fabrication of a Composite Tip Microneedle Array

A microneedle array was fabricated following a procedure similar to thatof Example 1, omitting step number 7, but otherwise performing theprocedure to step number 8, but not continuing to step number 9. Themicroneedles were then momentarily contacted to a solution ofapproximately 0.1% gentian violet in 2% aqueous carboxymethylcellulose,by positioning the entire array of needle tips to press into anapproximately 500 µm film of the gentian violet solution spread on asupporting substrate parallel to the substrate. Withdrawing the needleswas observed to form smaller “needles upon needles” of the gentianviolet solution. Upon drying as in step 9 of Example 1, these needleswere observed to be of comparable sharpness and rigidity to the needlesof Example 1, and would be expected to have different tip solubilitycharacteristics. Any of the exemplary polymers presented above arebelieved to be suitable for forming such composite tips, which areexpected to show various solubility behaviors under conditions of use.

Example 16 - Manufacture of Microneedle

A polymer coated substrate is contacted with a series of pins and pinsare allowed to remain in the polymer coating for a period of about 5seconds while a heated air (35° C.) is flowed across the substrate at arate of about 1.0 m/s. The pins are then retrated from the substrate ata rate of 5 mm/s to a distance of about 1 cm. About halfway through theretraction (approximately 10 seconds) an additional airflow isintroduced having a temperature of about 50° C. and a rate of about 2.0m/s.

It is to be understood that the above-described methods, formulations,and experiments are only illustrative of preferred embodiments of thepresent invention. Numerous modifications and alternative arrangementsmay be devised by those skilled in the art without departing from thespirit and scope of the present invention and the appended claims areintended to cover such modifications and arrangements.

Thus, while the present invention has been described above withparticularity and detail in connection with what is presently deemed tobe the most practical and preferred embodiments of the invention, itwill be apparent to those of ordinary skill in the art that numerousmodifications, including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

1. A method of administering an active agent transdermally comprising:providing a transdermal patch having a polymer base layer withmicroneedles projecting from a surface thereof, wherein the microneedlesare compositionally homogenous with the polymer base layer, and whereinsaid transdermal patch contains an active agent; and applying saidtransdermal patch to a skin surface of a subject.
 2. The method of claim1, wherein the active agent is delivered over a sustained period oftime.
 3. The method of claim 1, wherein the polymer base layer of thetransdermal patch is removed from the skin surface of the subject whileleaving the microneedles embedded in the skin surface.
 4. The method ofclaim 1, wherein the microneedles continue to deliver the active agentafter the polymer base layer is removed from the skin surface of thesubject.
 5. The method of claim 4, wherein the microneedles are hollow.6. The method of claim 1, wherein the microneedles are solid.
 7. Themethod of claim 6, wherein the active agent is loaded onto an exteriorsurface of the microneedles.
 8. The method of claim 1, wherein theactive agent is included in the polymer base layer.
 9. The method ofclaim 1, wherein the microneedles are regularly spaced on the polymerbase layer.
 10. The method of claim 5, wherein the active agent isloaded into the microneedles.
 11. The method of claim 1, wherein thetransdermal patch contains two or more active agents.
 12. The method ofclaim 1, wherein the active agent is incorporated into the microneedles.13. The method of claim 1, wherein the polymer is bio-absorbable. 14.The method of claim 1, wherein the polymer is biodegradable.
 15. Themethod of claim 1, further comprising removing said transdermal patchfrom the skin surface of a subject.
 16. The method of claim 15, whereinthe microneedles remain embedded in the skin surface after removal ofthe transdermal patch.
 17. The method of claim 1, wherein the polymerbase layer has a thickness from about 0.5 mm to about 5 mm.
 18. Themethod of claim 1, wherein the polymer is selected from the groupconsisting of polyvinyl alcohol, polyacrylates, polymers ofethylene-vinyl acetates, other acyl substituted cellulose acetates,polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride,polyethylene oxide, chlorosulphonate polyolefins, poly(vinyl imidazole),poly(valeric acid), poly butric acid, poly lactides, polyglycolides,polyanhydrides, polyorthoesters, polysaccharides, gelatin, and mixturesand copolymers thereof.
 19. The method of claim 1, wherein the activeagent is a nucleic acid.
 20. The method of claim 19, wherein the nucleicacid is single stranded DNA, double stranded DNA, single stranded RNA,double stranded RNA, or plasmid.
 21. A method for preparing amicroneedle array comprising: (i) applying a polymer solution onto asubstrate to form a base layer having a surface that is in contact withthe substrate and an exposed surface that is not in contact with thesubstrate; (ii) contacting the exposed surface of the base layer with anarray of pins for a period of time before retracting the array of pinsfrom the exposed surface of the base layer to form the microneedle arrayon the exposed surface of the base layer wherein the array of pins isretracted at a rate of 0.1 mm/s to 100 mm/s with an a heated airflow of0.1 m/s to 10 m/s at a temperature of 0° C. to 100° C.
 22. The method ofclaim 21 further comprising the step of incorporating an active agentinto the microneedle array.
 23. The method of claim 21 wherein themicroneedle array is incorporated into a transdermal patch.